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Efficacy and tolerability of conversion to monotherapy with lamotrigine compared with valproate and carbamazepine in patients with epilepsy
Epilepsy & Behavior Epilepsy & Behavior 5 (2004) 532–538 www.elsevier.com/locate/yebeh
Efficacy and tolerability of conversion to monotherapy with lamotrigine compared with valproate and carbamazepine in patients with epilepsyq Toufic A. Fakhoury,a,* Anne E. Hammer,b Alain Vuong,b and John A. Messenheimerb a
Department of Neurology, University of Kentucky, Albert Chandler Medical Center L-445, Lexington, KY, USA b GlaxoSmithKline, Research Triangle Park, NC, USA Received 7 January 2004; revised 14 April 2004; accepted 16 April 2004 Available online 20 May 2004
Abstract Objective. This randomized, open-label study was designed to compare the efficacy and tolerability of lamotrigine monotherapy with those of valproate and carbamazepine monotherapy in patients with epilepsy whose seizures were uncontrolled on their prestudy antiepileptic drug monotherapy. Methods. Patients meeting eligibility criteria were randomized 2:1 to lamotrigine:carbamazepine or lamotrigine:valproate. The treatment phase was divided into a 4-week dose-escalation phase (Weeks 1–4), during which lamotrigine, carbamazepine, or valproate was added to patientÕs prestudy monotherapy; an 8-week add-on phase (Weeks 5–12), during which patients were stabilized on both the study medication and their prestudy antiepileptic therapy; an 8-week withdrawal phase (Weeks 13–20), during which prestudy antiepileptic therapy could be withdrawn if clinically appropriate; and an 8-week monotherapy phase (Weeks 21–28), during which patients could be treated with study medication as monotherapy. Results. The numbers of patients randomized to the carbamazepine and valproate arms of the study were 144 (98 lamotrigine, 46 carbamazepine) and 158 (105 lamotrigine, 53 valproate), respectively. Successful monotherapy sustained for at least 7 weeks was achieved in comparable percentages of patients in the lamotrigine group (56%) and the carbamazepine group (54%) and in more patients in the lamotrigine group (49%) than the valproate group (40%). Among monotherapy completers, the percentage of patients with zero seizures during the monotherapy phase was comparable for lamotrigine (41%) and carbamazepine (30%) and significantly higher (P < 0:05) with lamotrigine (32%) than with valproate (11%). No differences between treatments were observed with respect to time to treatment failure or time to first seizure. Lamotrigine was also better tolerated than carbamazepine or valproate. Conclusion. Lamotrigine monotherapy was as effective as and better tolerated than carbamazepine or valproate monotherapy in patients whose seizures were uncontrolled on their prestudy antiepileptic drug monotherapy. 2004 Elsevier Inc. All rights reserved.
1. Introduction Monotherapy for epilepsy is as effective as or more effective than polytherapy; better tolerated; and associated with fewer drug interactions, lower costs, and better patient compliance and quality of life [1–7]. On the q The research described in this article was funded by GlaxoSmithKline, maker of lamotrigine. * Corresponding author. Fax: +859-257-4455. E-mail address: [email protected] (T.A. Fakhoury).
1525-5050/$ - see front matter 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2004.04.006
basis of these benefits, monotherapy is considered to be the goal in the pharmacologic management of epilepsy [1,8,9]. In fact, in their 2001 guidelines on the treatment of epilepsy, a panel of 45 US epilepsy experts recommended monotherapy not only as first-line treatment, but also as second-line therapy should an initial monotherapy fail [8]. Approximately half of the experts recommended trying a third monotherapy in the event of failure of the second monotherapy. The conventional antiepileptic drugs (AEDs) valproate and carbamazepine and the modern antiepileptic
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drug lamotrigine were among the options that the experts most commonly identified as optimal first-line or second-line monotherapy for generalized or localization-related epilepsies [8]. In some cases, particularly with the recommendations for second-line monotherapy, these selections were based on clinical experience with minimal data from clinical studies: although these three AEDs have been shown in randomized trials to be similarly effective as initial monotherapy in newly diagnosed patients [7,10–12], their comparative efficacy and tolerability as second-line monotherapy in patients failing an initial monotherapy have been less extensively studied. This randomized, open-label study was designed to compare the efficacy and tolerability of lamotrigine monotherapy with those of valproate and carbamazepine monotherapy in patients whose seizures were uncontrolled on their prestudy AED monotherapy.
2. Methods 2.1. Patients Patients P16 years of age diagnosed with epilepsy and experiencing any seizure type classifiable by the International Classification of Seizures [13] were eligible for the study if they had been treated with one AED for a minimum of 4 weeks prior to screening and had experienced at least two seizures during the 8 weeks before screening. Patients were determined by a clinician to be appropriate candidates for add-on therapy with lamotrigine, carbamazepine, or valproate and possible candidates for conversion to monotherapy with lamotrigine, carbamazepine, or valproate. Females were eligible only if they had a negative urine or serum pregnancy test at screening and agreed to use acceptable contraceptive methods during the study or were incapable of bearing children. Patients were excluded if they were treated with more than one AED at screening or if they were being treated with phenobarbital or primidone that could not be withdrawn over an 8-week period. All patients or their parents/guardians provided written informed consent. 2.2. Procedures The protocol for this open-label, randomized, parallel-group study (GlaxoSmithKline Protocol SCAA4011) was approved by institutional review boards or ethics committees for each of the 52 US study sites. The present study was part of a larger international protocol (GlaxoSmithKline Protocol SCAB3001) conducted in 17 other countries [14]. Data from the US centers considered separately were of interest because prescribing practices for AEDs, partic-
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ularly valproate, differ between the United States and other countries. In view of possible heterogeneity among countries in prestudy prescribing practices for AEDs, a report based on data from US centers was considered to be most useful to the prescribing physician in the United States. In addition, minor differences in the study protocol for US study centers versus study centers in other countries rendered a US-only assessment of interest. The study comprised a screening phase followed by a 28-week treatment phase. During the screening phase, patientsÕ eligibility for the study was determined, and patients were randomized to treatment with lamotrigine, carbamazepine, or valproate. Because the comparisons between lamotrigine and carbamazepine and between lamotrigine and valproate were of interest, the study was designed as two parallel arms: one arm in which patients were randomized 2:1 to lamotrigine:carbamazepine, and the second arm in which patients were randomized 2:1 to lamotrigine:valproate. Patients were randomized 2:1 in favor of lamotrigine to collect more tolerability data on lamotrigine monotherapy than a typical 1:1 randomization ratio would allow. The treatment phase was divided into a 4-week doseescalation phase (Weeks 1–4), during which lamotrigine, carbamazepine, or valproate was added to patientsÕ prestudy monotherapy; an 8-week add-on phase (Weeks 5–12), during which patients were stabilized on both the study medication and their prestudy antiepileptic therapy; an 8-week withdrawal phase (Weeks 13–20), during which prestudy AED therapy could be withdrawn if clinically appropriate; and an 8-week monotherapy phase (Weeks 21–28), during which patients could be treated with study medication as monotherapy. Patients whose prestudy AED could not be withdrawn could continue in the study on their prestudy AED plus study medication. Lamotrigine was added to the prestudy AED according to the dosing recommendations in the product label. Drug doses and escalation regimens for carbamazepine and valproate were determined by the clinician and were intended to be consistent with the dosing recommendations described in the product labels for these AEDs. Clinic visits occurred during Weeks 4, 12, 20, and 28. Patients completed all assessments through Week 28 even if they were withdrawn from randomized study medication. Efficacy endpoints included: • Percentage of patients receiving sustainable monotherapy (i.e., >7 weeks) with study medication. • Percentage of patients who were seizure-free or had P50% reduction in seizure frequency during the monotherapy phase (Weeks 21–28). These parameters were also calculated for the dose-escalation, add-on, and withdrawal phases. Seizure activity was recorded by patients or their parents/guardians in a daily diary kept throughout the study.
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• Time to treatment failure (defined as discontinuation of study medication because of lack of efficacy or poor tolerability) and time to first seizure. The primary safety endpoint was the incidence of adverse events (defined as any untoward medical occurrence regardless of its suspected cause) occurring at any time during the study. For each adverse event, the investigator recorded whether or not he or she considered it to be related to study medication.
3. Statistics Differences between groups in the percentages of patients with zero seizures and P50% reductions in seizure frequency were tested for each treatment arm by using the Mantel–Haenszel v2 test. The latter analysis was performed both for the intent-to-treat population and for monotherapy completers, defined as patients who completed the study through Week 28 with at least 7 continuous weeks of monotherapy on study medication. All other efficacy data were summarized for the intent-to-treat population only. The time to treatment failure and the time to first seizure were summarized by using Kaplan–Meier survival curves and compared between groups in each treatment arm by using the logrank test. All other data were summarized by using descriptive statistics, but no hypothesis testing was performed.
4. Results 4.1. Patients The numbers of patients randomized to the carbamazepine and valproate arms of the study were 144 (98 lamotrigine, 46 carbamazepine) and 158 (105 lamotrigine, 53 valproate), respectively. Demographics and baseline clinical characteristics were comparable among treatments (Table 1). The most common current AED monotherapies at the screening visit were phenytoin and valproate in the carbamazepine arms and carbamazepine and phenytoin in the valproate arm (Table 1). The majority of patients completed the study. Withdrawal of consent (i.e., withdrawal for administrative reasons) was the most common reason for premature discontinuation from the study in all groups (Table 1). Moreover, the majority of patients did not discontinue study medication prematurely. Adverse events were the most common reason for premature discontinuation of study medication in all treatment groups, but the incidence of premature discontinuation of study medication because of adverse events was lower with lamotrigine than with carbamazepine (14% vs 26% of discontinua-
tions) or valproate (13% vs 21% of discontinuations) (Table 1). 4.2. Incidence of successful switch to monotherapy In the carbamazepine arm, add-on therapy was attempted in all patients in the lamotrigine group (98/98) and all patients in the carbamazepine group (46/46). Withdrawal of prestudy AED was attempted in a slightly larger proportion of patients in the lamotrigine group (76%) than the carbamazepine group (67%) (Fig. 1). Successful monotherapy sustained for at least 7 weeks was achieved in comparable percentages of patients in the lamotrigine group (56%) and the carbamazepine group (54%) (Fig. 1). In the valproate arm, add-on therapy was attempted in 103 of 105 patients in the lamotrigine group and in 51 of 53 patients in the valproate group. Withdrawal of prestudy AED was attempted in more patients in the lamotrigine group (71%) than the valproate group (58%) (Fig. 1). Likewise, successful monotherapy sustained for at least 7 weeks was achieved in more patients in the lamotrigine group (49%) than the valproate group (40%) (Fig. 1). 4.3. Seizure control In the carbamazepine arm, the percentages of patients with at least 50% reduction from prestudy seizure frequency or zero seizures were comparable in the lamotrigine group and the carbamazepine group across study phases (i.e., dose-escalation, add-on, withdrawal, and monotherapy) (see Fig. 2 for data from monotherapy completers; intent-to-treat data were similar). In the valproate arm, the percentage of patients seizure-free was significantly higher in the lamotrigine group than the valproate group during the monotherapy phase (P < 0:05) (see Fig. 2 for data from monotherapy completers; intent-to-treat data were similar). The percentages of patients with at least 50% reduction from prestudy seizure frequency or zero seizures were significantly higher in the valproate group than the lamotrigine group during the dose-escalation phase (P < 0:05) (Fig. 2). 4.4. Median time to treatment failure and first seizure The median time to treatment failure did not differ between lamotrigine and the comparators (196.0 days for lamotrigine and 196.0 days for carbamazepine in the carbamazepine arm; 197.0 days for lamotrigine and 194.0 days for valproate in the valproate arm). Likewise, the median time to first seizure did not significantly differ between lamotrigine and the comparators (6.0 days for lamotrigine and 15.5 days for carbamazepine in the carbamazepine arm, P ¼ 0:17; 8.0 days for lamotrigine and 7.0 days for valproate in the valproate arm, P ¼ 0:56).
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Table 1 Demographics, baseline clinical characteristics, and patient disposition Carbamazepine arm
Mean (SD) age Number female Mean (SD) number of seizures during 2 months prior to screening Seizure type during 2 months prior to screening, n(%) Simple partial Complex partial Partial with secondary generalization Other Study completion status, n(%) Discontinued Completed Reason for discontinuation from the study, n(%) Death Consent withdrawn Lost to follow-up Protocol violation Other Number(%) discontinuing study medication prematurely Adverse event Death Consent withdrawn Lost to follow-up Protocol violation Other Current antiepileptic drug at screening, n(%) Any Phenytoin Divalproex sodium Sodium valproate Carbamazepine Gabapentin Phenobarbital Topiramate Clonazepam Primidone Felbamate Mephenytoin
Valproate arm
Lamotrigine (n ¼ 98)
Carbamazepine (n ¼ 46)
Lamotrigine (n ¼ 105)
Valproate (n ¼ 53)
41.0 (14.8) 58 (59%) 14.2 (37.6)
40.3 (12.9) 25 (54%) 17.7 (50.1)
38.3 (13.3) 59 (56%) 6.6 (11.0)
39.0 (12.7) 33 (62%) 8.3 (14.3)
25 56 39 24
15 32 14 10
35 65 30 20
15 38 19 11
(26%) (57%) (40%) (24%)
(33%) (70%) (30%) (22%)
(33%) (62%) (29%) (19%)
(28%) (72%) (36%) (21%)
19 (19%) 79 (81%) n ¼ 19 2 (11%) 7 (37%) 4 (21%) 4 (21%) 2 (11%) 29 (30%) 14 (14%) 1 (1%) 4 (4%) 3 (3%) 5 (5%) 2 (2%)
7 (15%) 39 (85%) n¼7 0 (0%) 4 (57%) 2 (29%) 1 (14%) 0 (0%) 16 (35%) 12 (26%) 0 (0%) 2 (4%) 1 (2%) 1 (2%) 0 (0%)
28 (27%) 77 (73%) n ¼ 28 1 (4%) 15 (54%) 10 (36%) 2 (7%) 0 (0%) 32 (30%) 14 (13%) 1 (<1%) 8 (8%) 6 (6%) 3 (3%) 0 (0%)
16 (30%) 37 (70%) n ¼ 16 0 (0%) 7 (44%) 5 (31%) 1 (6%) 3 (19%) 24 (46%) 11 (21%) 0 (0%) 5 (10%) 4 (8%) 1 (2%) 3 (6%)
98 (100%) 38 (39%) 39 (40%) 6 (6%) 0 (0%) 7 (7%) 3 (3%) 3 (3%) 1 (1%) 1 (1%) 0 (0%) 0 (0%)
46 (100%) 22 (48%) 11 (24%) 6 (13%) 1 (2%) 3 (7%) 2 (4%) 1 (2%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
105 (100%) 30 (29%) 0 (0%) 1 (<1%) 59 (56%) 7 (7%) 4 (4%) 2 (2%) 0 (0%) 0 (0%) 1 (<1%) 1 (<1%)
52 (98%) 17 (32%) 0 (0%) 0 (0%) 28 (53%) 3 (6%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 0 (0%) 0 (0%)
Fig. 1. Percentage of patients in whom add-on therapy was attempted, add-on therapy was successful, and monotherapy sustained for at least 7 weeks was achieved with study medication.
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T.A. Fakhoury et al. / Epilepsy & Behavior 5 (2004) 532–538
Fig. 2. Percentage of patients with at least a 50% reduction in seizure frequency and seizure-free as a function of study phase (dose-escalation, add-on, withdrawal, and monotherapy). Data from patients completing the study on at least 7 weeks of successful monotherapy are shown. Results for the intent-to-treat population were similar.
4.5. Adverse events Lamotrigine was better tolerated than carbamazepine or valproate. In the carbamazepine arm, the percentages
of patients with at least one drug-related adverse event were 62% in the lamotrigine group and 72% in the carbamazepine group (Table 2). The most common drug-related adverse events with both treatments were
Table 2 Number (%) of patients with adverse events considered by the investigator to be drug-relateda Carbamazepine arm
Any event Dizziness Somnolence Tremor Asthenia Nausea Alopecia Blurred vision Diplopia Headache a
Valproate arm
Lamotrigine (n ¼ 98)
Carbamazepine (n ¼ 46)
Lamotrigine (n ¼ 105)
Valproate (n ¼ 53)
61 (62%) 17 (17%) 13 (13%) 8 (8%) 6 (6%) 1 (1%) 3 (3%) 1 (1%) 0 (0%) 5 (5%)
33 (72%) 11 (24%) 12 (26%) 6 (13%) 7 (15%) 4 (9%) 1 (2%) 6 (13%) 6 (13%) 4 (9%)
56 (53%) 16 (15%) 11 (10%) 5 (5%) 6 (6%) 6 (6%) 1 (<1%) 11 (10%) 7 (7%) 11 (10%)
37 (70%) 6 (11%) 7 (13%) 11 (21%) 5 (9%) 7 (13%) 6 (11%) 1 (2%) 3 (6%) 4 (8%)
Drug-related adverse events reported in at least 10% of patients in any dosing group are listed.
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dizziness (lamotrigine, 17% of patients; carbamazepine, 24% of patients) and somnolence (lamotrigine, 13% of patients; carbamazepine, 26% of patients). In the valproate arm, the percentages of patients with at least one drug-related adverse event were 53% in the lamotrigine group and 70% in the valproate group (Table 2). The most common drug-related adverse event in the lamotrigine group was dizziness (15% of patients vs 11% for valproate). The most common drug-related adverse events in the valproate group were tremor (21% of patients vs 5% with lamotrigine), nausea (13% vs 6% with lamotrigine), and somnolence.
5. Discussion Data from this randomized study in patients with primarily partial-onset seizures show that when prestudy epilepsy AED monotherapy (most often phenytoin, carbamazepine, or valproate) was unsuccessful, lamotrigine monotherapy was successfully substituted in approximately half of patients. Furthermore, lamotrigine monotherapy effectively controlled seizures. Among monotherapy completers, the percentage of patients with zero seizures during the monotherapy phase was comparable between lamotrigine (41%) and carbamazepine (30%) and significantly higher (P < 0:05) with lamotrigine (32%) than valproate (11%). No differences between treatments were observed for time to treatment failure or time to first seizure. While lamotrigine was at least as effective at controlling seizures as carbamazepine or valproate, it appeared to be better tolerated than both of these older AEDs. The overall incidences of drug-related adverse events and of specific drug-related adverse events were lower with lamotrigine than with either carbamazepine or valproate, with the exception of dizziness in the valproate arm, which was reported slightly more often with lamotrigine (15% of patients) than with valproate (11% of patients). Moreover, the incidence of premature discontinuation of study medication because of adverse events was lower with lamotrigine than with carbamazepine (14% vs 26%) or valproate (13% vs 21%). The data from this study extend previous findings showing that lamotrigine monotherapy can be successfully substituted for other AEDs [15–17]. For example, in one study of 126 patients with refractory epilepsy, 68% of patients completed dose-escalation, add-on, and monotherapy phases of open-label treatment with lamotrigine 200 to 500 mg/day [15]. More than half of patients (53%) experienced at least a 50% reduction in seizure frequency during lamotrigine monotherapy compared with prestudy baseline. In another study of 347 patients with seizures not fully controlled with valproate, carbamazepine, phenytoin, or phenobarbital,
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41% of patients had at least 50% reduction in seizures during addition of lamotrigine to their prestudy regimen and thereby met the criterion for attempting to transition to lamotrigine monotherapy; 23% of patients completed an add-on phase to achieve lamotrigine monotherapy; and 17% completed 12 weeks of lamotrigine monotherapy [17]. Unlike valproate, carbamazepine has not been compared with lamotrigine in head-to-head monotherapy substitution trials published to date. However, lamotrigine monotherapy has been shown to be at least as effective as carbamazepine monotherapy in adult and elderly patients with newly diagnosed seizures [18,19]. In one 48-week, double-blind trial, lamotrigine monotherapy (150 mg/day) compared with carbamazepine monotherapy (600 mg/day) was associated with a higher incidence of successful completion of the maintenancetherapy phase, a comparable degree of seizure control, and a lower incidence of neurologic adverse events as well as withdrawals because of adverse events [18]. A similar pattern of results was obtained in an open-label trial comparing lamotrigine (100 or 200 mg/day) and carbamazepine (600 mg/day) monotherapy in patients with newly diagnosed or recurrent epilepsy [19]. Besides providing additional data on the efficacy and tolerability of lamotrigine monotherapy compared with older AED monotherapies, the data from the current study reinforce currently accepted epilepsy management strategies, which are guided by the goal of controlling seizures with monotherapy whenever possible [7–9]. Compared with polytherapy, monotherapy is better tolerated, is associated with fewer drug interactions and better patient compliance and quality of life; and costs less [1–7]. Previous studies show that seizures can be effectively controlled in approximately half of patients on the first monotherapy that is tried and in an additional 10 to 25% of patients with the second monotherapy [2–7,20]. Noting that the currently available AED monotherapies are generally not distinguishable on the basis of efficacy data from clinical trials, Brodie identifies several other factors, such as mechanism of action, spectrum of activity, neuropsychiatric profile, sedative burden, longterm side effects, and ease of dosing, that also need to be considered in choosing among AEDs for monotherapy [6]. Many of these features are not directly assessed in clinical trials such as the current one. Taking into account these features and others, Brodie considers lamotrigine to have a better profile as AED monotherapy than the conventional medications phenobarbital, phenytoin, carbamazepine, and valproate [6]. Specific advantages of lamotrigine included better tolerability and predictable kinetics. This assessment dovetails well with the results of the current study. In summary, in this randomized trial, lamotrigine monotherapy was as effective as carbamazepine
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monotherapy or valproate monotherapy and better tolerated than either carbamazepine or valproate in patients whose seizures were uncontrolled on their prestudy AED monotherapy. The results of this study should be interpreted in the context of its open-label design, which does not permit unequivocal attribution of patientsÕ improvements to study medication.
References [1] Guberman A. Monotherapy or polytherapy for epilepsy? Can J Neurol Sci 1998;25:S3–8. [2] Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic–clonic seizures. N Engl J Med 1985;313:145–51. [3] Beghi E, Tognoni G. Prognosis of epilepsy in newly referred patients: a multicenter prospective study. Epilepsia 1988;29:236–43. [4] Schmidt D. Reduction of two-drug therapy in intractable epilepsy. Epilepsia 1983;24:368–76. [5] Theodore WH, Porter RJ. Removal of sedative–hypnotic antiepileptic drugs from the regimens of patients with intractable epilepsy. Ann Neurol 1983;13:320–4. [6] Brodie MJ. Monostars: an aid to choosing an antiepileptic drug as monotherapy. Epilepsia 1999;40(Suppl. 76):S17–22. [7] Schneiderman JH. Monotherapy versus polytherapy in epilepsy: a framework for patient management. Can J Neurol Sci 1998;25:S9– 13. [8] Karceski S, Morrell M, Carpenter D. The expert consensus guidelines series: treatment of epilepsy. Epilepsy Behav 2001;2: A1–50. [9] Schmidt D. Strategies to prevent overtreatment with antiepileptic drugs in patients with epilepsy. Epilepsy Res 2002;52:61–9.
[10] Collaborative Group for the Study of Epilepsy. Prognosis of epilepsy in newly referred patients: a multicenter prospective study of the effects of monotherapy on the long-term course of epilepsy. Epilepsia 1992;33:45–51. [11] Heller AJ, Chesterman P, Elwes RDC, et al. Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial. J Neurol Neurosurg Psychiatry 1995;58:44–50. [12] de Silva M, MacArdle B, McGowan M. Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy. Lancet 1996;347:709–13. [13] Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1989;30:389–99. [14] Fakhoury T, Li H, Moorat AM, et al. Quality of life in patients with epilepsy switched to monotherapy with lamotrigine or valproate. Epilepsia 2001;42(Suppl. 2):91. [15] Jozwiak S, Terczynski A. Open study evaluating lamotrigine efficacy and safety in add-on treatment and consecutive monotherapy in patients with carbamazepine- or valproate-resistant epilepsy. Seizure 2000;9:486–92. [16] Gilliam F, Vazquez B, Sackellares JC, et al. An active-control trial of lamotrigine monotherapy for partial seizures. Neurology 1998;51:1018–25. [17] Brodie MJ, Yuen AW. Lamotrigine substitution study: evidence for synergism with sodium valproate? Epilepsy Res 1997;26:423–32. [18] Brodie MJ, Richens A, Yuen AWC, et al. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet 1995;345:476–9. [19] Reunanen M, Dam M, Yuen AWC. A randomized open multicentre comparative trial of lamotrigine and carbamazepine as monotherapy in patients with newly diagnosed or recurrent epilepsy. Epilepsy Res 1996;23:149–55. [20] Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314–9.
Efficacy and tolerability of conversion to monotherapy with lamotrigine compared with valproate and carbamazepine in patients with epilepsyq Toufic A. Fakhoury,a,* Anne E. Hammer,b Alain Vuong,b and John A. Messenheimerb a
Department of Neurology, University of Kentucky, Albert Chandler Medical Center L-445, Lexington, KY, USA b GlaxoSmithKline, Research Triangle Park, NC, USA Received 7 January 2004; revised 14 April 2004; accepted 16 April 2004 Available online 20 May 2004
Abstract Objective. This randomized, open-label study was designed to compare the efficacy and tolerability of lamotrigine monotherapy with those of valproate and carbamazepine monotherapy in patients with epilepsy whose seizures were uncontrolled on their prestudy antiepileptic drug monotherapy. Methods. Patients meeting eligibility criteria were randomized 2:1 to lamotrigine:carbamazepine or lamotrigine:valproate. The treatment phase was divided into a 4-week dose-escalation phase (Weeks 1–4), during which lamotrigine, carbamazepine, or valproate was added to patientÕs prestudy monotherapy; an 8-week add-on phase (Weeks 5–12), during which patients were stabilized on both the study medication and their prestudy antiepileptic therapy; an 8-week withdrawal phase (Weeks 13–20), during which prestudy antiepileptic therapy could be withdrawn if clinically appropriate; and an 8-week monotherapy phase (Weeks 21–28), during which patients could be treated with study medication as monotherapy. Results. The numbers of patients randomized to the carbamazepine and valproate arms of the study were 144 (98 lamotrigine, 46 carbamazepine) and 158 (105 lamotrigine, 53 valproate), respectively. Successful monotherapy sustained for at least 7 weeks was achieved in comparable percentages of patients in the lamotrigine group (56%) and the carbamazepine group (54%) and in more patients in the lamotrigine group (49%) than the valproate group (40%). Among monotherapy completers, the percentage of patients with zero seizures during the monotherapy phase was comparable for lamotrigine (41%) and carbamazepine (30%) and significantly higher (P < 0:05) with lamotrigine (32%) than with valproate (11%). No differences between treatments were observed with respect to time to treatment failure or time to first seizure. Lamotrigine was also better tolerated than carbamazepine or valproate. Conclusion. Lamotrigine monotherapy was as effective as and better tolerated than carbamazepine or valproate monotherapy in patients whose seizures were uncontrolled on their prestudy antiepileptic drug monotherapy. 2004 Elsevier Inc. All rights reserved.
1. Introduction Monotherapy for epilepsy is as effective as or more effective than polytherapy; better tolerated; and associated with fewer drug interactions, lower costs, and better patient compliance and quality of life [1–7]. On the q The research described in this article was funded by GlaxoSmithKline, maker of lamotrigine. * Corresponding author. Fax: +859-257-4455. E-mail address: [email protected] (T.A. Fakhoury).
1525-5050/$ - see front matter 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2004.04.006
basis of these benefits, monotherapy is considered to be the goal in the pharmacologic management of epilepsy [1,8,9]. In fact, in their 2001 guidelines on the treatment of epilepsy, a panel of 45 US epilepsy experts recommended monotherapy not only as first-line treatment, but also as second-line therapy should an initial monotherapy fail [8]. Approximately half of the experts recommended trying a third monotherapy in the event of failure of the second monotherapy. The conventional antiepileptic drugs (AEDs) valproate and carbamazepine and the modern antiepileptic
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drug lamotrigine were among the options that the experts most commonly identified as optimal first-line or second-line monotherapy for generalized or localization-related epilepsies [8]. In some cases, particularly with the recommendations for second-line monotherapy, these selections were based on clinical experience with minimal data from clinical studies: although these three AEDs have been shown in randomized trials to be similarly effective as initial monotherapy in newly diagnosed patients [7,10–12], their comparative efficacy and tolerability as second-line monotherapy in patients failing an initial monotherapy have been less extensively studied. This randomized, open-label study was designed to compare the efficacy and tolerability of lamotrigine monotherapy with those of valproate and carbamazepine monotherapy in patients whose seizures were uncontrolled on their prestudy AED monotherapy.
2. Methods 2.1. Patients Patients P16 years of age diagnosed with epilepsy and experiencing any seizure type classifiable by the International Classification of Seizures [13] were eligible for the study if they had been treated with one AED for a minimum of 4 weeks prior to screening and had experienced at least two seizures during the 8 weeks before screening. Patients were determined by a clinician to be appropriate candidates for add-on therapy with lamotrigine, carbamazepine, or valproate and possible candidates for conversion to monotherapy with lamotrigine, carbamazepine, or valproate. Females were eligible only if they had a negative urine or serum pregnancy test at screening and agreed to use acceptable contraceptive methods during the study or were incapable of bearing children. Patients were excluded if they were treated with more than one AED at screening or if they were being treated with phenobarbital or primidone that could not be withdrawn over an 8-week period. All patients or their parents/guardians provided written informed consent. 2.2. Procedures The protocol for this open-label, randomized, parallel-group study (GlaxoSmithKline Protocol SCAA4011) was approved by institutional review boards or ethics committees for each of the 52 US study sites. The present study was part of a larger international protocol (GlaxoSmithKline Protocol SCAB3001) conducted in 17 other countries [14]. Data from the US centers considered separately were of interest because prescribing practices for AEDs, partic-
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ularly valproate, differ between the United States and other countries. In view of possible heterogeneity among countries in prestudy prescribing practices for AEDs, a report based on data from US centers was considered to be most useful to the prescribing physician in the United States. In addition, minor differences in the study protocol for US study centers versus study centers in other countries rendered a US-only assessment of interest. The study comprised a screening phase followed by a 28-week treatment phase. During the screening phase, patientsÕ eligibility for the study was determined, and patients were randomized to treatment with lamotrigine, carbamazepine, or valproate. Because the comparisons between lamotrigine and carbamazepine and between lamotrigine and valproate were of interest, the study was designed as two parallel arms: one arm in which patients were randomized 2:1 to lamotrigine:carbamazepine, and the second arm in which patients were randomized 2:1 to lamotrigine:valproate. Patients were randomized 2:1 in favor of lamotrigine to collect more tolerability data on lamotrigine monotherapy than a typical 1:1 randomization ratio would allow. The treatment phase was divided into a 4-week doseescalation phase (Weeks 1–4), during which lamotrigine, carbamazepine, or valproate was added to patientsÕ prestudy monotherapy; an 8-week add-on phase (Weeks 5–12), during which patients were stabilized on both the study medication and their prestudy antiepileptic therapy; an 8-week withdrawal phase (Weeks 13–20), during which prestudy AED therapy could be withdrawn if clinically appropriate; and an 8-week monotherapy phase (Weeks 21–28), during which patients could be treated with study medication as monotherapy. Patients whose prestudy AED could not be withdrawn could continue in the study on their prestudy AED plus study medication. Lamotrigine was added to the prestudy AED according to the dosing recommendations in the product label. Drug doses and escalation regimens for carbamazepine and valproate were determined by the clinician and were intended to be consistent with the dosing recommendations described in the product labels for these AEDs. Clinic visits occurred during Weeks 4, 12, 20, and 28. Patients completed all assessments through Week 28 even if they were withdrawn from randomized study medication. Efficacy endpoints included: • Percentage of patients receiving sustainable monotherapy (i.e., >7 weeks) with study medication. • Percentage of patients who were seizure-free or had P50% reduction in seizure frequency during the monotherapy phase (Weeks 21–28). These parameters were also calculated for the dose-escalation, add-on, and withdrawal phases. Seizure activity was recorded by patients or their parents/guardians in a daily diary kept throughout the study.
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• Time to treatment failure (defined as discontinuation of study medication because of lack of efficacy or poor tolerability) and time to first seizure. The primary safety endpoint was the incidence of adverse events (defined as any untoward medical occurrence regardless of its suspected cause) occurring at any time during the study. For each adverse event, the investigator recorded whether or not he or she considered it to be related to study medication.
3. Statistics Differences between groups in the percentages of patients with zero seizures and P50% reductions in seizure frequency were tested for each treatment arm by using the Mantel–Haenszel v2 test. The latter analysis was performed both for the intent-to-treat population and for monotherapy completers, defined as patients who completed the study through Week 28 with at least 7 continuous weeks of monotherapy on study medication. All other efficacy data were summarized for the intent-to-treat population only. The time to treatment failure and the time to first seizure were summarized by using Kaplan–Meier survival curves and compared between groups in each treatment arm by using the logrank test. All other data were summarized by using descriptive statistics, but no hypothesis testing was performed.
4. Results 4.1. Patients The numbers of patients randomized to the carbamazepine and valproate arms of the study were 144 (98 lamotrigine, 46 carbamazepine) and 158 (105 lamotrigine, 53 valproate), respectively. Demographics and baseline clinical characteristics were comparable among treatments (Table 1). The most common current AED monotherapies at the screening visit were phenytoin and valproate in the carbamazepine arms and carbamazepine and phenytoin in the valproate arm (Table 1). The majority of patients completed the study. Withdrawal of consent (i.e., withdrawal for administrative reasons) was the most common reason for premature discontinuation from the study in all groups (Table 1). Moreover, the majority of patients did not discontinue study medication prematurely. Adverse events were the most common reason for premature discontinuation of study medication in all treatment groups, but the incidence of premature discontinuation of study medication because of adverse events was lower with lamotrigine than with carbamazepine (14% vs 26% of discontinua-
tions) or valproate (13% vs 21% of discontinuations) (Table 1). 4.2. Incidence of successful switch to monotherapy In the carbamazepine arm, add-on therapy was attempted in all patients in the lamotrigine group (98/98) and all patients in the carbamazepine group (46/46). Withdrawal of prestudy AED was attempted in a slightly larger proportion of patients in the lamotrigine group (76%) than the carbamazepine group (67%) (Fig. 1). Successful monotherapy sustained for at least 7 weeks was achieved in comparable percentages of patients in the lamotrigine group (56%) and the carbamazepine group (54%) (Fig. 1). In the valproate arm, add-on therapy was attempted in 103 of 105 patients in the lamotrigine group and in 51 of 53 patients in the valproate group. Withdrawal of prestudy AED was attempted in more patients in the lamotrigine group (71%) than the valproate group (58%) (Fig. 1). Likewise, successful monotherapy sustained for at least 7 weeks was achieved in more patients in the lamotrigine group (49%) than the valproate group (40%) (Fig. 1). 4.3. Seizure control In the carbamazepine arm, the percentages of patients with at least 50% reduction from prestudy seizure frequency or zero seizures were comparable in the lamotrigine group and the carbamazepine group across study phases (i.e., dose-escalation, add-on, withdrawal, and monotherapy) (see Fig. 2 for data from monotherapy completers; intent-to-treat data were similar). In the valproate arm, the percentage of patients seizure-free was significantly higher in the lamotrigine group than the valproate group during the monotherapy phase (P < 0:05) (see Fig. 2 for data from monotherapy completers; intent-to-treat data were similar). The percentages of patients with at least 50% reduction from prestudy seizure frequency or zero seizures were significantly higher in the valproate group than the lamotrigine group during the dose-escalation phase (P < 0:05) (Fig. 2). 4.4. Median time to treatment failure and first seizure The median time to treatment failure did not differ between lamotrigine and the comparators (196.0 days for lamotrigine and 196.0 days for carbamazepine in the carbamazepine arm; 197.0 days for lamotrigine and 194.0 days for valproate in the valproate arm). Likewise, the median time to first seizure did not significantly differ between lamotrigine and the comparators (6.0 days for lamotrigine and 15.5 days for carbamazepine in the carbamazepine arm, P ¼ 0:17; 8.0 days for lamotrigine and 7.0 days for valproate in the valproate arm, P ¼ 0:56).
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Table 1 Demographics, baseline clinical characteristics, and patient disposition Carbamazepine arm
Mean (SD) age Number female Mean (SD) number of seizures during 2 months prior to screening Seizure type during 2 months prior to screening, n(%) Simple partial Complex partial Partial with secondary generalization Other Study completion status, n(%) Discontinued Completed Reason for discontinuation from the study, n(%) Death Consent withdrawn Lost to follow-up Protocol violation Other Number(%) discontinuing study medication prematurely Adverse event Death Consent withdrawn Lost to follow-up Protocol violation Other Current antiepileptic drug at screening, n(%) Any Phenytoin Divalproex sodium Sodium valproate Carbamazepine Gabapentin Phenobarbital Topiramate Clonazepam Primidone Felbamate Mephenytoin
Valproate arm
Lamotrigine (n ¼ 98)
Carbamazepine (n ¼ 46)
Lamotrigine (n ¼ 105)
Valproate (n ¼ 53)
41.0 (14.8) 58 (59%) 14.2 (37.6)
40.3 (12.9) 25 (54%) 17.7 (50.1)
38.3 (13.3) 59 (56%) 6.6 (11.0)
39.0 (12.7) 33 (62%) 8.3 (14.3)
25 56 39 24
15 32 14 10
35 65 30 20
15 38 19 11
(26%) (57%) (40%) (24%)
(33%) (70%) (30%) (22%)
(33%) (62%) (29%) (19%)
(28%) (72%) (36%) (21%)
19 (19%) 79 (81%) n ¼ 19 2 (11%) 7 (37%) 4 (21%) 4 (21%) 2 (11%) 29 (30%) 14 (14%) 1 (1%) 4 (4%) 3 (3%) 5 (5%) 2 (2%)
7 (15%) 39 (85%) n¼7 0 (0%) 4 (57%) 2 (29%) 1 (14%) 0 (0%) 16 (35%) 12 (26%) 0 (0%) 2 (4%) 1 (2%) 1 (2%) 0 (0%)
28 (27%) 77 (73%) n ¼ 28 1 (4%) 15 (54%) 10 (36%) 2 (7%) 0 (0%) 32 (30%) 14 (13%) 1 (<1%) 8 (8%) 6 (6%) 3 (3%) 0 (0%)
16 (30%) 37 (70%) n ¼ 16 0 (0%) 7 (44%) 5 (31%) 1 (6%) 3 (19%) 24 (46%) 11 (21%) 0 (0%) 5 (10%) 4 (8%) 1 (2%) 3 (6%)
98 (100%) 38 (39%) 39 (40%) 6 (6%) 0 (0%) 7 (7%) 3 (3%) 3 (3%) 1 (1%) 1 (1%) 0 (0%) 0 (0%)
46 (100%) 22 (48%) 11 (24%) 6 (13%) 1 (2%) 3 (7%) 2 (4%) 1 (2%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
105 (100%) 30 (29%) 0 (0%) 1 (<1%) 59 (56%) 7 (7%) 4 (4%) 2 (2%) 0 (0%) 0 (0%) 1 (<1%) 1 (<1%)
52 (98%) 17 (32%) 0 (0%) 0 (0%) 28 (53%) 3 (6%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 0 (0%) 0 (0%)
Fig. 1. Percentage of patients in whom add-on therapy was attempted, add-on therapy was successful, and monotherapy sustained for at least 7 weeks was achieved with study medication.
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Fig. 2. Percentage of patients with at least a 50% reduction in seizure frequency and seizure-free as a function of study phase (dose-escalation, add-on, withdrawal, and monotherapy). Data from patients completing the study on at least 7 weeks of successful monotherapy are shown. Results for the intent-to-treat population were similar.
4.5. Adverse events Lamotrigine was better tolerated than carbamazepine or valproate. In the carbamazepine arm, the percentages
of patients with at least one drug-related adverse event were 62% in the lamotrigine group and 72% in the carbamazepine group (Table 2). The most common drug-related adverse events with both treatments were
Table 2 Number (%) of patients with adverse events considered by the investigator to be drug-relateda Carbamazepine arm
Any event Dizziness Somnolence Tremor Asthenia Nausea Alopecia Blurred vision Diplopia Headache a
Valproate arm
Lamotrigine (n ¼ 98)
Carbamazepine (n ¼ 46)
Lamotrigine (n ¼ 105)
Valproate (n ¼ 53)
61 (62%) 17 (17%) 13 (13%) 8 (8%) 6 (6%) 1 (1%) 3 (3%) 1 (1%) 0 (0%) 5 (5%)
33 (72%) 11 (24%) 12 (26%) 6 (13%) 7 (15%) 4 (9%) 1 (2%) 6 (13%) 6 (13%) 4 (9%)
56 (53%) 16 (15%) 11 (10%) 5 (5%) 6 (6%) 6 (6%) 1 (<1%) 11 (10%) 7 (7%) 11 (10%)
37 (70%) 6 (11%) 7 (13%) 11 (21%) 5 (9%) 7 (13%) 6 (11%) 1 (2%) 3 (6%) 4 (8%)
Drug-related adverse events reported in at least 10% of patients in any dosing group are listed.
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dizziness (lamotrigine, 17% of patients; carbamazepine, 24% of patients) and somnolence (lamotrigine, 13% of patients; carbamazepine, 26% of patients). In the valproate arm, the percentages of patients with at least one drug-related adverse event were 53% in the lamotrigine group and 70% in the valproate group (Table 2). The most common drug-related adverse event in the lamotrigine group was dizziness (15% of patients vs 11% for valproate). The most common drug-related adverse events in the valproate group were tremor (21% of patients vs 5% with lamotrigine), nausea (13% vs 6% with lamotrigine), and somnolence.
5. Discussion Data from this randomized study in patients with primarily partial-onset seizures show that when prestudy epilepsy AED monotherapy (most often phenytoin, carbamazepine, or valproate) was unsuccessful, lamotrigine monotherapy was successfully substituted in approximately half of patients. Furthermore, lamotrigine monotherapy effectively controlled seizures. Among monotherapy completers, the percentage of patients with zero seizures during the monotherapy phase was comparable between lamotrigine (41%) and carbamazepine (30%) and significantly higher (P < 0:05) with lamotrigine (32%) than valproate (11%). No differences between treatments were observed for time to treatment failure or time to first seizure. While lamotrigine was at least as effective at controlling seizures as carbamazepine or valproate, it appeared to be better tolerated than both of these older AEDs. The overall incidences of drug-related adverse events and of specific drug-related adverse events were lower with lamotrigine than with either carbamazepine or valproate, with the exception of dizziness in the valproate arm, which was reported slightly more often with lamotrigine (15% of patients) than with valproate (11% of patients). Moreover, the incidence of premature discontinuation of study medication because of adverse events was lower with lamotrigine than with carbamazepine (14% vs 26%) or valproate (13% vs 21%). The data from this study extend previous findings showing that lamotrigine monotherapy can be successfully substituted for other AEDs [15–17]. For example, in one study of 126 patients with refractory epilepsy, 68% of patients completed dose-escalation, add-on, and monotherapy phases of open-label treatment with lamotrigine 200 to 500 mg/day [15]. More than half of patients (53%) experienced at least a 50% reduction in seizure frequency during lamotrigine monotherapy compared with prestudy baseline. In another study of 347 patients with seizures not fully controlled with valproate, carbamazepine, phenytoin, or phenobarbital,
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41% of patients had at least 50% reduction in seizures during addition of lamotrigine to their prestudy regimen and thereby met the criterion for attempting to transition to lamotrigine monotherapy; 23% of patients completed an add-on phase to achieve lamotrigine monotherapy; and 17% completed 12 weeks of lamotrigine monotherapy [17]. Unlike valproate, carbamazepine has not been compared with lamotrigine in head-to-head monotherapy substitution trials published to date. However, lamotrigine monotherapy has been shown to be at least as effective as carbamazepine monotherapy in adult and elderly patients with newly diagnosed seizures [18,19]. In one 48-week, double-blind trial, lamotrigine monotherapy (150 mg/day) compared with carbamazepine monotherapy (600 mg/day) was associated with a higher incidence of successful completion of the maintenancetherapy phase, a comparable degree of seizure control, and a lower incidence of neurologic adverse events as well as withdrawals because of adverse events [18]. A similar pattern of results was obtained in an open-label trial comparing lamotrigine (100 or 200 mg/day) and carbamazepine (600 mg/day) monotherapy in patients with newly diagnosed or recurrent epilepsy [19]. Besides providing additional data on the efficacy and tolerability of lamotrigine monotherapy compared with older AED monotherapies, the data from the current study reinforce currently accepted epilepsy management strategies, which are guided by the goal of controlling seizures with monotherapy whenever possible [7–9]. Compared with polytherapy, monotherapy is better tolerated, is associated with fewer drug interactions and better patient compliance and quality of life; and costs less [1–7]. Previous studies show that seizures can be effectively controlled in approximately half of patients on the first monotherapy that is tried and in an additional 10 to 25% of patients with the second monotherapy [2–7,20]. Noting that the currently available AED monotherapies are generally not distinguishable on the basis of efficacy data from clinical trials, Brodie identifies several other factors, such as mechanism of action, spectrum of activity, neuropsychiatric profile, sedative burden, longterm side effects, and ease of dosing, that also need to be considered in choosing among AEDs for monotherapy [6]. Many of these features are not directly assessed in clinical trials such as the current one. Taking into account these features and others, Brodie considers lamotrigine to have a better profile as AED monotherapy than the conventional medications phenobarbital, phenytoin, carbamazepine, and valproate [6]. Specific advantages of lamotrigine included better tolerability and predictable kinetics. This assessment dovetails well with the results of the current study. In summary, in this randomized trial, lamotrigine monotherapy was as effective as carbamazepine
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monotherapy or valproate monotherapy and better tolerated than either carbamazepine or valproate in patients whose seizures were uncontrolled on their prestudy AED monotherapy. The results of this study should be interpreted in the context of its open-label design, which does not permit unequivocal attribution of patientsÕ improvements to study medication.
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